VA Class:CN105

AHFS Class:

• Non-selective alpha-Adrenergic Blocking Agents 12:16.04.04

Generic Name(s):

• Ergotamine Tartrate

Ergotamine is a naturally occurring ergot alkaloid.

Vascular Headaches

Ergotamine tartrate is used to prevent or abort vascular headaches, including migraine and cluster headaches.

In patients with severe attacks of migraine which are not responsive to a mild analgesic, ergotamine has been effective in 80-90% of patients when taken during the prodrome or immediately after the onset of an attack. However, other placebo-controlled trials of ergotamine have yielded inconsistent results regarding efficacy of the drug in the treatment of migraine headaches.121 Some experts state that ergotamine therapy may be considered in selected patients with moderate to severe acute migraine attacks, although the drug is associated with a higher incidence of adverse effects compared with drugs such as sumatriptan or nonsteroidal anti-inflammatory agents (NSAIAs).121 Because of the likelihood of adverse effects, ergotamine generally should not be used for prophylactic management of migraine headaches.

Ergot derivatives generally are not preferred for terminating an acute cluster headache because of their slow onset of action compared with other therapies such as sumatriptan or oxygen.134,136,141,142 However, ergot derivatives have been used short term (e.g., 2-3 weeks) on a scheduled basis to suppress a series of attacks and reduce the duration of a cluster cycle.134,135,141,142 Some experts state that ergotamine tartrate may be administered 30-60 minutes prior to an expected attack in patients who have consistent attack patterns.135,142 Prophylactic administration of ergotamine tartrate at bedtime may be particularly useful in selected patients with nocturnal attacks.134,135,136,139,140,141 Ergotamine tartrate should not be used for chronic daily therapy of vascular headaches.138,139,140 Verapamil is considered the drug of choice for long-term prevention of cluster headaches.134,135,136,137,141,142

Ergotamine tartrate is not effective in the treatment of muscle contraction headaches.

The relative efficacy of the various routes of administration of ergotamine tartrate has not been established; sublingual administration usually is considered the least effective. Rectal administration of the combination of ergotamine tartrate and caffeine in a suppository is preferred to oral therapy in patients with nausea or vomiting. Since cluster headaches have no prodrome and are briefer than migraine headaches, oral inhalation of ergotamine tartrate (oral inhaler no longer commercially available in the US) may be preferred at the onset of the cluster headache.

Ergotamine tartrate is used orally or rectally in combination with caffeine. Caffeine's cerebral vasoconstrictor effect reportedly is additive with that of ergotamine, but the results of one study suggest that the principal value of caffeine in this combination is related to its ability to increase GI absorption of ergotamine tartrate. There is conflicting evidence regarding the efficacy of this combination in the treatment of acute migraine attacks.121 Some clinicians question the value of the combination because caffeine may keep patients awake and sleep can contribute to the relief of migraine. Fixed combinations of ergotamine tartrate and belladonna alkaloids (no longer commercially available in the US) may be useful in some patients to lessen nausea and vomiting which often occur during migraine attacks or that are caused by ergotamine. (For further information on management and classification of migraine headache, see Vascular Headaches: General Principles in Migraine Therapy, under Uses in Sumatriptan 28:32.28.)

Administration

Ergotamine tartrate is given sublingually.138 A combination of ergotamine tartrate and caffeine may be administered orally, or rectally as a suppository.139,140 If the suppositories become softened, they should be chilled in ice-cold water to solidify before removing the foil wrapper.139

To be most effective, ergotamine tartrate should be administered as soon as possible after the first symptoms of a vascular headache (i.e., during the prodromal phase if there is one or at the beginning of an attack).138,139,140 The amount of drug required and the speed and degree of relief are thought to be directly related to the promptness with which the drug is started. After the initial dose is administered, the patient should lie down and relax in a quiet, darkened room. Ergotamine should not be administered within 24 hours of a selective serotonin agonist (e.g., sumatriptan).115,116,144,145 (See Drug Interactions: Selective Serotonin Agonists.)

Dosage

Vascular Headaches

Oral and Sublingual Dosage

The usual adult oral dosage of ergotamine tartrate in fixed combination with caffeine (Cafergot^®) is 2 mg (2 tablets) initially, followed by 1 mg at 30-minute intervals until the attack has abated or a total of 6 mg has been given.140 The total oral dosage should not exceed 6 mg (6 tablets) per attack and 10 mg (10 tablets) in 1 week.140

The recommended initial dose of sublingual ergotamine tartrate (Ergomar^®) is 2 mg (1 tablet) placed under the tongue; if relief is not attained, additional doses of 2 mg may be administered at 30-minute intervals.138 The total sublingual dosage should not exceed 6 mg (3 tablets) in any 24-hour period and 10 mg (5 tablets) in 1 week.138

For short-term prophylaxis of cluster headaches in patients with short cluster periods, ergotamine tartrate has been given orally or sublingually in a dosage of 3-4 mg daily (in divided doses) for periods of up to 3 weeks.135,142 Ergotamine tartrate may be administered 30-60 minutes prior to an expected attack in patients who have consistent attack patterns.135,142 In selected patients with nocturnal attacks of cluster headaches, some clinicians recommend that 1-2 mg of ergotamine tartrate be given orally at bedtime to help patients sleep more restfully.140,141,142 Patients receiving ergotamine tartrate for short-term prophylaxis must be monitored carefully to avoid excessive weekly dosages.142 The manufacturer states that due consideration should be given to the recommended maximum weekly dosage.140

Although safety and efficacy in children have not been definitely established, some clinicians recommend 1 mg of ergotamine tartrate orally or sublingually in older children and adolescents at the onset of an attack, followed by 1 mg every 30 minutes as needed up to a maximum of 3 mg per attack.14,133

Rectal Dosage

When administered rectally as a suppository in combination with caffeine, the initial adult dose of ergotamine tartrate is 2 mg at the start of an attack.139 If necessary, a second 2-mg dose may be given after 1 hour.139 The maximum rectal dosage is 4 mg for one attack; total weekly dosage should not exceed 10 mg.139 In selected patients with nocturnal cluster headaches, 1-2 mg of ergotamine tartrate may be given rectally at bedtime on a short-term basis.137,139,142 When used for prophylaxis, consideration should be given to the recommended maximum weekly dosage.139,142

The most common adverse effects of ergotamine tartrate are nausea and vomiting occurring in about 10% of patients receiving the drug.112 Abdominal pain; weakness in the legs; muscle pain or stiffness in the extremities, neck, or shoulders; and numbness and tingling of fingers and toes are common and usually do not require discontinuance of the drug. However, if these symptoms are persistent, ergotamine should be stopped.

Cardiovascular Effects

There is a wide variation in sensitivity to the vasoconstrictor effects of ergotamine and, although adverse effects are most common with long-term therapy using higher than usual doses, vasospasm also has occurred rarely with short-term therapy or usual doses of the drug. Vasoconstriction may cause coronary insufficiency with precipitation or aggravation of angina pectoris and possibly myocardial infarction and death. Cold, numb, painful extremities with or without paresthesia have occurred; pulses of the affected extremity are often diminished or absent. Claudication of the legs may occur. When the drug is discontinued, symptoms of impaired peripheral circulation are usually reversible. Gangrene of extremities may develop but is rare with usual doses in patients without peripheral vascular disease or other contraindications. Other adverse effects due to vasospasm have included transient monocular blindness, bilateral papillitis, ischemic colitis, renal artery vasoconstriction, and cyanosis with partial necrosis of the tongue. Arterial spasm, which may affect any blood vessel, also may occur in patients receiving ergotamine. Precordial distress and pain, ECG changes, transient sinus tachycardia or bradycardia, and hypertension have been reported in some patients receiving ergotamine.

Heart Valvulopathy and Associated Effects

Long-term administration (chronic or intermittent administration for several to about 20 years or more) of ergot alkaloids (e.g., ergotamine,100,103,106 methysergide [no longer commercially available in the US])100,101,102,104,105,107,109,111,113 has been associated with abnormal heart valve findings (similar to those associated with use of some amphetamines [e.g., dexfenfluramine, fenfluramine {both no longer commercially available in the US}]),108 including echocardiographic and pathologic features (that sometimes required open heart surgery).100,101,104 However, limited data indicate that development of these adverse cardiac effects is not directly related to dosage or duration of drug therapy.101 The incidence of adverse cardiac effects in patients receiving chronic administration of ergot alkaloids is not known either because lesions may not be investigated or, alternatively, they may be attributed to different etiology (e.g., rheumatic heart disease).100 Limited data indicate that abnormal heart valve findings may occur in about 3.6% of patients receiving chronic methysergide therapy.100,101

Unlike cardiac valve disease associated with carcinoid syndrome (affecting mainly the right side of the heart) or with rheumatic heart disease (affecting usually the left side of the heart), ergot alkaloid-induced heart valve disease may affect valves in any pattern.100 Abnormal heart valve findings associated with ergot alkaloids include moderate to severe aortic and/or mitral regurgitation, severe tricuspid regurgitation, mild to moderate pulmonary regurgitation, and mild or moderate to severe mitral stenosis.100,101,102,103,104,105,106,107,110 Fibrotic thickening of the aortic,100,101,102,107,139 mitral,100,101,102,107,110,139 pulmonary,139 and tricuspid100,139 valves and chordae tendineae101,102,103,104,107 were reported in many patients with ergot alkaloid-induced cardiac valvulopathy. Retroperitoneal and pleuropulmonary fibrosis also have been reported in patients receiving methysergide107,109,110,111 and, rarely, in patients receiving ergotamine.106,139 Ergot alkaloid-induced endocardial fibrosis resembles the fibrosis of carcinoid syndrome100,101,103 while microscopic findings of these valvulopathies were different from those associated with chronic rheumatic valvulitis.100,102 It has been recommended that patients who have heart murmurs (which may indicate valvulopathy and/or endocardial fibrosis) either before or during long-term ergot alkaloid therapy should undergo an echocardiogram (ECHO); drug therapy should be discontinued promptly since discontinuance of ergot alkaloid therapy may result in regression of the murmurs in many patients.100,101,106

The mechanism of these ergot-alkaloid-associated adverse cardiac effects has not been elucidated.100 However, it has been suggested that similar to carcinoid syndrome, these cardiac abnormalities may be related to serotonergic alterations induced by the drugs.100,101,102,103,105,107

Nervous System Effects

Patients who receive excessive doses of ergotamine daily for prolonged periods may become dependent on the drug and often experience mental depression, fatigue, and increased frequency of headache. When the drug is discontinued, these patients experience rebound headache which is somewhat different from the original migraine or cluster headache. Although it is relieved temporarily by taking another dose of ergotamine, the drug should be discontinued in these patients; after the drug is stopped, a severe headache persists for a few days and then subsides. The possibility of headaches resulting from caffeine withdrawal should also be considered in patients who have received combination products. Other adverse nervous system effects reported in patients receiving ergotamine include paresthesia and vertigo.138,139,140

GI Effects

Nausea, vomiting, abdominal pain, diarrhea, and epigastric discomfort have been reported in patients receiving ergotamine. Rectal or anal ulcer resulting from overuse of ergotamine tartrate and caffeine suppositories has been reported.139

Other Adverse Effects

Weakness in the legs; muscle pain; stiffness in the extremities, neck, or shoulders; polydipsia; and fatigue have occurred in patients receiving ergotamine. Localized edema and pruritus may occur rarely in sensitive patients.

Precautions and Contraindications

Patients receiving ergotamine should be instructed to report symptoms such as persistent paresthesia and chest, muscle, or abdominal pain to their physicians and to not exceed the maximum recommended dosage. If signs and symptoms of impaired circulation occur, ergotamine should be discontinued and the affected extremities should be kept warm. Withdrawal of the drug is often the only treatment required. In patients with severe peripheral vasoconstriction and impending tissue necrosis, IV sodium nitroprusside should be used for vasospasm; intra-arterial tolazoline hydrochloride also has been used. IV heparin and 10% dextran 40 in 5% dextrose injection may be given in conjunction with sodium nitroprusside or tolazoline hydrochloride to prevent vascular stasis and thrombosis. Regional sympathetic blockade is of no proven value.

Retroperitoneal and pleuropulmonary fibrosis has been reported in patients receiving ergotamine tartrate.106,139 Fibrotic thickening of the aortic, mitral, tricuspid, and/or pulmonary valves also has been reported rarely with long-term administration of the drug.100,139 Therefore, ergotamine tartrate should not be administered on a chronic daily basis.139 (See Dosage and Administration: Dosage.)

Patients receiving an ergot alkaloid (e.g., ergotamine, methysergide [no longer commercially available in the US]) should be examined regularly for the development of valvulopathy and development of fibrotic or vascular complications, and appropriate tests (e.g., echocardiogram, laboratory tests, radiographic examination) should be performed if signs or symptoms of valvulopathy, fibrosis, or vascular insufficiency occur.100,109,113,114

Because of the risk of acute ergot toxicity (ergotism) and other serious adverse vasospastic effects, use of ergotamine tartrate is contraindicated in patients receiving potent inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4 (e.g., certain HIV protease inhibitors, macrolide antibiotics, azole-derivative anti-infective agents).124,125,126,127,138,139,140 (See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.) Serious or life-threatening peripheral ischemia characterized by vasospasm and ischemia of the extremities, in some cases requiring amputation, has been reported in patients receiving ergotamine tartrate concomitantly with potent CYP3A4 inhibitors.127,138,139,140 Cerebral ischemia, including at least one fatality, also has been reported rarely in patients receiving ergotamine tartrate concomitantly with HIV protease inhibitor therapy.138,139,140 Although such effects have not been reported with concomitant use of ergotamine tartrate and less potent CYP3A4 inhibitors (e.g., saquinavir, nefazodone, fluconazole, fluoxetine, fluvoxamine, grapefruit juice, zileuton, metronidazole, clotrimazole), the potential for serious toxicity should be considered when these and other similar drugs or foods are used concomitantly.138,139,140

Ergotamine tartrate is contraindicated in patients with sepsis, peripheral vascular disease (e.g., thromboangiitis obliterans, luetic arteritis, severe arteriosclerosis, thrombophlebitis, Raynaud's disease), coronary artery disease, impaired hepatic or renal function, malnutrition, and severe hypertension. The drug is also contraindicated in patients with known hypersensitivity to ergot alkaloids or any ingredient in the formulation.

Pediatric Precautions

Safety and efficacy of ergotamine in children have not been established.

Carcinogenicity

Studies to determine the carcinogenic potential of ergotamine have not been performed to date.

Pregnancy and Lactation

Pregnancy

Retarded fetal growth and increases in intrauterine death and resorption were reported in animals receiving ergotamine.112 It has been postulated that such fetotoxicity is associated with drug-induced increases in uterine motility and vasoconstriction in the placental vasculature.112 Ergotamine is contraindicated in women who are or may become pregnant.

Lactation

Ergotamine is distributed into milk and may cause vomiting, diarrhea, weak pulse, unstable blood pressure, and seizures in nursing infants.128,129,138,139,140 Although ergot alkaloids have been reported to inhibit maternal pituitary prolactin secretion, decreased lactation has not been reported to date with ergotamine.128,138,139,140 Because of the potential for serious adverse reactions to ergotamine in nursing infants,128,129,138,139,140 a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.138,139,140

Methysergide

The potential exists for excessive vasoconstriction to occur when ergotamine is used concomitantly with methysergide (no longer commercially available in the US).143 In patients who are receiving methysergide for prophylaxis, the dose of ergotamine tartrate may have to be decreased (by about 50%) and the frequency of ergotamine tartrate administration should be kept at a minimum.

Nicotine

Because nicotine may result in vasoconstriction in some patients, thereby increasing the risk of an enhanced ischemic response to ergot alkaloids, ergotamine tartrate and nicotine should not be used concomitantly.138,139,140

Propranolol

One case of severe peripheral vasoconstriction with pain and cyanosis has been reported in a patient who received propranolol orally and high doses of ergotamine in a rectal suppository concurrently for the treatment of migraine. Although several patients have received these drugs concomitantly without adverse effects, caution should be used during simultaneous administration of propranolol and high doses of ergot alkaloids.

Selective Serotonin Agonists

Because ergot alkaloids (e.g., ergotamine, dihydroergotamine, methysergide) have been reported to cause prolonged vasospastic reactions and preliminary data suggest that the vasoconstrictor effects of these drugs may be additive with those of selective serotonin agonists (e.g., sumatriptan),115,116,117,118,119,144,145 the manufacturers of selective serotonin agonists recommend that these drugs and ergot alkaloids not be used within 24 hours of each other.115,116,144,145 However, in a placebo-controlled study in patients with a history of migraine who were receiving dihydroergotamine prophylaxis, no clinical evidence of a drug interaction was observed when subcutaneous sumatriptan was used to treat breakthrough migraine attacks.120

Sympathomimetic Agents

Concomitant use of ergotamine with sympathomimetic agents (e.g., pressor agents) may result in extreme elevation of blood pressure and should be avoided.138,139,140

Drugs Affecting Hepatic Microsomal Enzymes

Certain macrolide antibiotics (e.g., erythromycin, clarithromycin, troleandomycin), HIV protease inhibitors (e.g., ritonavir, nelfinavir, indinavir), and azole-derivative anti-infective agents (e.g., itraconazole, ketoconazole) may alter the metabolism of ergotamine via inhibition of cytochrome P-450 (CYP) isoenzyme 3A4, resulting in increased serum concentrations of ergotamine and therefore increasing the risk of vasospasm, which may lead to potentially fatal cerebral ischemia and/or ischemia of the extremities.123,124,125,126,127,138,139,140 Therefore, concomitant use of ergotamine tartrate with potent CYP 3A4 inhibitors is contraindicated.124,125,126,127,138,139,140 (See Cautions: Precautions and Contraindications.)

Acute Toxicity

Manifestations

In addition to the adverse effects which may occur with usual doses or prolonged administration of high doses (especially adverse vasospastic effects, nausea, and vomiting), acute overdosage of ergotamine may cause lassitude, impaired mental function, confusion, depression, drowsiness, delirium, severe dyspnea, hypotension, hypertension, rapid and weak pulse, unconsciousness, spasms of the limbs, seizures (rarely), shock, and death. The possibility of adverse effects from other ingredients in combination products should be considered. Toxicity is likely to occur in patients with sepsis or in those with renal or hepatic impairment.112 Patients with peripheral vascular disease are especially at risk of developing peripheral ischemia associated with ergotamine.112 Acute toxicity usually has been reported at ergotamine tartrate dosages exceeding 15 mg in 24 hours or 40 mg in a few days; however, toxicity has been reported in some patients receiving less than 5 mg of the drug.112 Death occurred in one 14-month-old child who ingested 12 mg of ergotamine tartrate and 1.2 g of caffeine. Another 13-month-old child recovered after ingesting approximately 15 mg of ergotamine tartrate, 1 g of phenobarbital, and 5 mg of belladonna.

Treatment

Management of ergotamine overdosage consists of general supportive measures and symptomatic therapy following discontinuance of the drug. If ingestion of the drug is recent and the patient is conscious, emesis should be induced. If the patient is comatose, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents. Activated charcoal and a saline cathartic such as magnesium sulfate may be given. For management of overdosage following rectal administration of ergotamine tartrate in combination with caffeine, the manufacturer states that administration of an enema may aid in removal of the drug.139 Peripheral vasospasm is managed by keeping the affected extremities warm. If vasospasm persists or ischemic tissue damage is imminent, sodium nitroprusside, tolazoline hydrochloride, heparin, and/or dextran 40 may be administered. (See Cautions: Precautions and Contraindications.) Seizures may be treated with IV diazepam. For nausea and vomiting, atropine or an antiemetic (e.g., a phenothiazine) may be used.112 Ergotamine is eliminated by dialysis.112

Pharmacology

Ergotamine has complex pharmacologic effects. In therapeutic doses, ergotamine causes peripheral vasoconstriction (if the vascular tone is low) primarily by stimulating α-adrenergic receptors; however, the drug causes vasodilation in very hypertonic vessels. With higher doses, ergotamine is also a competitive α-adrenergic blocker, but this effect is somewhat masked by the drug's α-adrenergic agonist activity. With therapeutic doses, ergotamine also inhibits reuptake of norepinephrine, thereby maintaining a high concentration of circulating norepinephrine and increasing ergotamine's vasoconstrictor action. Ergotamine has greater vasoconstrictor activity than the other ergot alkaloids but less α-adrenergic blocking activity than dihydroergotamine. Ergotamine is a weaker antagonist of serotonin (5-hydroxytryptamine) than is methysergide, but ergotamine does reduce the increased rate of platelet aggregation induced by serotonin. The mechanism by which ergotamine aborts vascular headaches is probably direct vasoconstriction of the dilated carotid artery bed with a concomitant decrease in the amplitude of pulsations; the drug's effects on catecholamines and serotonin are also at least partly involved.

The effects of ergotamine on blood pressure are unpredictable but are usually minimal in the doses used in the management of migraine headaches. The drug usually causes bradycardia due to increased vagal activity and possibly decreased sympathetic tone in the CNS and direct myocardial depression. Ergotamine stimulates the chemoreceptor trigger zone and may cause nausea and vomiting. Although ergotamine has oxytocic effects, the drug is much less effective than ergonovine in stimulating uterine contractions. Ergotamine may inhibit prolactin secretion.

Pharmacokinetics

Absorption

Following oral administration, absorption of ergotamine tartrate is quite variable; peak plasma concentrations are attained within 0.5-3 hours. Orally administered ergotamine tartrate undergoes first-pass metabolism. In one study, the rate and extent of absorption of ergotamine tartrate were greater, especially within the first hour after oral administration, when the drug was given with caffeine than when given alone; caffeine may increase the dissolution rate of ergotamine, which would be particularly important at intestinal pH. Well-controlled studies are not available comparing the onset of action or rate and degree of absorption of ergotamine tartrate following various routes of administration. The onset of action in patients with vascular headaches probably depends on how promptly the drug is given after the onset of the headache.

Distribution

Ergotamine crosses the blood-brain barrier and is distributed into milk.

Elimination

Following a single oral dose of radiolabeled ergotamine tartrate in individuals with normal renal and hepatic function in one study, plasma concentrations of total radioactivity declined in a biphasic manner with an average half-life of 2.7 hours in the initial phase and 21 hours in the terminal phase.

Ergotamine, particularly the peptide portion of the molecule, is extensively metabolized in the liver by the cytochrome P-450 (CYP) enzyme system, mainly by the 3A4 isoenzyme; 90% of the metabolites are excreted in bile. The unchanged drug is erratically secreted in the saliva and only traces of unchanged drug are excreted in urine and feces.112 Following a single oral dose of ergotamine in individuals with normal renal and hepatic function in one study, only about 4% of the dose was excreted in urine within 96 hours; the remainder of the dose was presumably excreted in feces. Ergotamine is eliminated by dialysis.

Chemistry and Stability

Chemistry

Ergotamine is a naturally occurring ergot alkaloid. Ergotamine tartrate occurs as colorless crystals or a white to yellowish-white, crystalline powder and is slightly soluble in water and in alcohol. Water solubility is slightly increased by addition of caffeine or a slight excess of tartaric acid. Ergotamine has a pK_a of 6.3. In aqueous solutions, ergotamine and its salts undergo isomerization; at equilibrium, a 3:2 ratio of ergotamine and its inactive epimer ergotaminine is present.

Stability

Preparations of ergotamine tartrate should be stored in light-resistant containers. Oral tablets containing ergotamine tartrate and caffeine should be stored at 15-30°C.140 Ergotamine tartrate sublingual tablets should be stored at 20-25°C but may be exposed to temperatures ranging from 15-30°C.138 Suppositories containing ergotamine tartrate and caffeine should be stored at a temperature of 2-8°C.139

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